Exploring potential genetic correlation and causality between cathepsins and neurodegenerative diseases: Insight from Mendelian randomization analyses.

Background: Previous research has exhibited a potential association between cathepsins and neurodegenerative diseases (NDDs). Nevertheless, the causal relationships between cathepsins and different types of NDDs remain inadequately clear. Objective: We aim to explore the genetically correlation and causality between 4 NDDs and 9 cathepsins based on genome-wide association study platform. Methods: Cathepsin B, E, F, G, H, L2, O, S, and Z and four NDDs types, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and dementia with Lewy bodies, were obtained from large-scale genome-wide summary data. To explore potential interactive roles of these cathepsins in the pathogenesis of NDDs, we applied two-sample bidirectional univariable Mendelian randomization (MR) and multivariable MR, with inverse variance weighting as the primary statistical approach. Results: The univariable MR analysis revealed one positive and two negative causal effects between genetic liability in nine cathepsins and four NDDs. Reverse univariable MR analysis identified one negative causal link. Furthermore, the multivariable MR analysis not only confirmed two significant associations observed in the univariable analysis but also revealed a new positive effect. Conclusions: Our findings demonstrate that several cathepsins are causally associated with different NDDs, offering new insights into the underlying mechanisms of neurodegeneration. These results may contribute to the development of novel diagnostic and therapeutic strategies for managing neurodegeneration.